Leukemia Initiation in MLL-ENL Mediated Leukemogenesis
Author
Summary, in English
In the blood system, knowledge on the regulation of hematopoietic stem cells (HSCs) and their immature progeny has provided roadmaps of differentiation. Such information can also have a value to understand the etiology of hematological cancers, since clinical heterogeneity and prognostic therapeutic outcomes have been proposed to associate with the specific developmental stage from which the transformed cells originate. Chromosomal rearrangements involving the mixed lineage leukemia-1 (MLL1) gene result in chimeric fusion proteins that can act as transcriptional regulators, and represents a family of recurrent initiating events in human leukemia. MLL1 translocations can result in diseases with different phenotypic representation, but the underlying reason for why seemingly similar translocation products can cause myeloid, lymphoid or mixed leukemia remain unknown.
Various hematopoietic progenitor cells can serve as a candidate cells for transformation and we addressed this issue of “leukemia initiating competence” in article I, where we developed a conditional (doxycycline inducible) transgenic mouse model of the human chimeric transcription factor Mixed Lineage Leukemia-Eleven Nineteen Leukemia (MLL-ENL). Prospective isolations of hematopoietic progenitor cells at distinct stages of differentiation, followed by their adoptive transfer under continuous fusion gene expression permitted us to monitor their leukemia-initiation and competence. In our work, acute myeloid leukemia (AML) could initiate from several different progenitor subsets. Our study highlighted the importance of using highly defined cell types, as developmentally close myeloid progenitor subpopulations showed dramatically different leukemic competence. HSCs however, were resistant to leukemic transformation and displayed reduced proliferative and repopulating capabilities. In addition, we failed to observe lymphoid leukemia development, which is consistent with most experimental mouse models trying to assess MLL-fusion mediated transformation. This seemingly discrepant finding when compared to human leukemias might be the result of underlying factors such as the instructive/permissive nature of MLL-fusions and/or the normal differentiation potential of the target cell. To this end, we in article II demonstrated that leukemia competence in the mouse was lost upon definitive lymphoid commitment, as only very early lymphoid progenitors (DN1 T cells and BLPs) could develop leukemia; in those cases by evoking a latent myeloid potential of the target cells which ultimately resulted in AML. We further demonstrated that not only could co-occurring mutations impact on the latency of leukemia development, but also that the sequence by which the mutations are acquired can have significant influence on the lineage representation of the developing leukemia. As a final part of this work, we assessed the impact of transdifferentiation on leukemia initiation and found that C/EBPB-mediated transdifferentiation could result in acquisition of leukemia competence in otherwise leukemia incompetent lymphoid committed cells. As transdifferentiation recently has been proposed for therapeutic approaches, these results raise concerns regarding their general feasibility.
Finally, in article III, we evaluated the impact of the ribosomal stress pathway on leukemia initiation, a mechanism that potentially could represent a general approach to target oncogenic cells. We demonstrated that genetic targeting of the 5S RNP-MDM2-TRP53 ribosomal stress pathway delays leukemia initiation significantly, but did not provide significant survival advantages in already established leukemia. Therefore, the ribosomal stress pathway holds limited therapeutic value for AML treatment.
Various hematopoietic progenitor cells can serve as a candidate cells for transformation and we addressed this issue of “leukemia initiating competence” in article I, where we developed a conditional (doxycycline inducible) transgenic mouse model of the human chimeric transcription factor Mixed Lineage Leukemia-Eleven Nineteen Leukemia (MLL-ENL). Prospective isolations of hematopoietic progenitor cells at distinct stages of differentiation, followed by their adoptive transfer under continuous fusion gene expression permitted us to monitor their leukemia-initiation and competence. In our work, acute myeloid leukemia (AML) could initiate from several different progenitor subsets. Our study highlighted the importance of using highly defined cell types, as developmentally close myeloid progenitor subpopulations showed dramatically different leukemic competence. HSCs however, were resistant to leukemic transformation and displayed reduced proliferative and repopulating capabilities. In addition, we failed to observe lymphoid leukemia development, which is consistent with most experimental mouse models trying to assess MLL-fusion mediated transformation. This seemingly discrepant finding when compared to human leukemias might be the result of underlying factors such as the instructive/permissive nature of MLL-fusions and/or the normal differentiation potential of the target cell. To this end, we in article II demonstrated that leukemia competence in the mouse was lost upon definitive lymphoid commitment, as only very early lymphoid progenitors (DN1 T cells and BLPs) could develop leukemia; in those cases by evoking a latent myeloid potential of the target cells which ultimately resulted in AML. We further demonstrated that not only could co-occurring mutations impact on the latency of leukemia development, but also that the sequence by which the mutations are acquired can have significant influence on the lineage representation of the developing leukemia. As a final part of this work, we assessed the impact of transdifferentiation on leukemia initiation and found that C/EBPB-mediated transdifferentiation could result in acquisition of leukemia competence in otherwise leukemia incompetent lymphoid committed cells. As transdifferentiation recently has been proposed for therapeutic approaches, these results raise concerns regarding their general feasibility.
Finally, in article III, we evaluated the impact of the ribosomal stress pathway on leukemia initiation, a mechanism that potentially could represent a general approach to target oncogenic cells. We demonstrated that genetic targeting of the 5S RNP-MDM2-TRP53 ribosomal stress pathway delays leukemia initiation significantly, but did not provide significant survival advantages in already established leukemia. Therefore, the ribosomal stress pathway holds limited therapeutic value for AML treatment.
Department/s
Publishing year
2016
Language
English
Publication/Series
Lund University Faculty of Medicine Doctoral Dissertation Series
Volume
2016:19
Document type
Dissertation
Publisher
Division of Molecular Hematology (DMH)
Topic
- Hematology
Keywords
- Hematopoiesis
- Luekemia
- Cell of origin
- Leukemia Initiation
Status
Published
Supervisor
ISBN/ISSN/Other
- ISSN: 1652-8220
- ISBN: 978-91-7619-245-0
Defence date
24 February 2016
Defence time
13:00
Defence place
Belfragesalen BMC D15, Klinikgatan 32, Lund.
Opponent
- Scott Armstrong (Prof)